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Fusion Loop Peptide of the West Nile Virus Envelope Protein Is Essential for Pathogenesis and Is Recognized by a Therapeutic Cross-Reactive Human Monoclonal Antibody

Hameeda Sultana^*, Harald G. Foellmer^*, Girish Neelakanta^*, Theodore Oliphant, Michael Engle^¶, Michel Ledizet, Manoj N. Krishnan^*, Nathalie Bonafé, Karen G. Anthony, Wayne A. Marasco^||, Paul Kaplan, Ruth R. Montgomery, Michael S. Diamond^,¶, Raymond A. Koski and Erol Fikrig^*,#

^*Section of Infectious Diseases and Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; L2 Diagnostics, New Haven, CT 06511; Department of Molecular Microbiology and ^¶Departments of Medicine, Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63130; ^||Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA 02115; and ^#Howard Hughes Medical Institute, Chevy Chase, MD 20815

West Nile virus is an emerging pathogen that can cause fatal neurological disease. A recombinant human mAb, mAb11, has been described as a candidate for the prevention and treatment of West Nile disease. Using a yeast surface display epitope mapping assay and neutralization escape mutant, we show that mAb11 recognizes the fusion loop, at the distal end of domain II of the West Nile virus envelope protein. Ab mAb11 cross-reacts with all four dengue viruses and provides protection against dengue (serotypes 2 and 4) viruses. In contrast to the parental West Nile virus, a neutralization escape variant failed to cause lethal encephalitis (at higher infectious doses) or induce the inflammatory responses associated with blood-brain barrier permeability in mice, suggesting an important role for the fusion loop in viral pathogenesis. Our data demonstrate that an intact West Nile virus fusion loop is critical for virulence, and that human mAb11 targeting this region is efficacious against West Nile virus infection. These experiments define the molecular determinant on the envelope protein recognized by mAb11 and demonstrate the importance of this region in causing West Nile encephalitis.

Address correspondence and reprint requests to Dr. Erol Fikrig, Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, S525A, 300 Cedar Street, New Haven, CT 06520-8022. E-mail address: erol.fikrig{at}yale.edu.